Integrative Proteome- and Phenome-Wide Assessment Uncovers Causal Protein Drivers and Drug Targets for Heterogeneous...

Interpreting proteomic associations with chronic kidney disease (CKD) is challenging due to the disease's clinical heterogeneity and complex overlap with systemic conditions. We present a framework that identifies causal circulating protein drivers of CKD and delineates their subtype-specific and systemic effects using electronic health record (EHR) data at biobank scale. Using proteome-wide Mendelian randomization, we instrumented cis-acting protein quantitative trait loci for 2,807 circulating proteins and tested them against detailed, EHR-based kidney function outcomes in 464,631 Million Veteran Program participants. Proteins were mapped to nine kidney disease subtypes defined by genome-wide association meta-analyses from the Million Veteran Program, UK Biobank, and FinnGen. Phenome-wide association studies across 1,020 traits distinguished renal versus extra-renal associations. This integrative strategy prioritizes 93 proteins with proteome-wide significance for kidney outcomes, demonstrates subtype-specific relevance, exposes systemic associations, and maps therapeutic targets to nominate candidates for drug development and repurposing.